THE EFFECT OF LEUKEMIA INHIBITORY FACTOR (LIF) ON TROPHOBLAST DIFFERENTIATION - A POTENTIAL ROLE IN HUMAN IMPLANTATION

Leukemia inhibitory factor (LIF) is a multifunctional glycoprotein str ongly associated with normal implantation in the mouse. We have recent ly determined that LIF is expressed in the human endometrium in a mens trual cycle dependent manner. Maximal expression is observed between d ays 19 and 25 of the menstrual cycle, coinciding with the time of huma n implantation. In this study we have utilized purified cultures of hu man cytotrophoblasts to examine the effects of LIF on several morpholo gic and biochemical markers of the trophoblastic differentiation. We p urified human cytotrophoblasts from term placentae and cultured them w ith and without LIF (10 ng/mL). The secretion of human CG, oncofetal f ibronectin, and progesterone were measured at 24, 48, 72, and 96 h. No rthern blot analysis was used to assess messenger RNA (mRNA) expressio n of beta hCG and oncofetal fibronectin. We found that LIF markedly de creased trophoblast production of hCG protein at 72 and 96 h, as well as expression of beta hCG mRNA. LIF also significantly increased the e xpression of oncofetal fibronectin mRNA and secretion of the protein. LIF did not affect steroidogenic activity of cultured trophoblasts, as determined by progesterone production. These biochemical changes are characteristic of cytotrophoblast differentiation toward an anchoring extravillous phenotype. Thus, LIF appears to be an important regulator of human embryonic implantation by directly modulating trophoblast di fferentiation.